Resistance to infection by microorganisms makes use of non-specific functions (enzyme action, pH, epithelial wall) and of the adaptive immune responses of B and T lymphocytic cells.
The non-specific functions prevent invasion by the majority of attacking agents. However, when this first line of defense capitulates, the phagocytic system comes into operation, destroys the infectious agents and stimulates the immunity functions conferred by the B and T cells.
Any abnormality, hereditary or acquired, of the phagocytic system has serious consequences, since even microorganisms which are normally of low pathogenicity evade it and trigger recurrent infections.
Moreover, any deficiency in the immune system itself, at T or B cell level, leads to an enhanced susceptibility to intra- or extracellular viral and bacterial infections. These deficiencies may be hereditary or acquired (e.g. AIDS=elective T cell deficiency). Most people suffering from these deficiencies are subject to infection by opportunistic organisms (bacteria, protozoa, and the like).
In all cases of immunosuppression, it is hence desirable that the phagocytic system is as effective as possible, in order to limit the consequences of external attack. Of secondary importance under normal conditions, phagocytosis takes on an essential character when the B and T immune response weakens.
Among cells associated with the immune response, the polymorphonuclear leukocytes are of special interest in the context of combating infections. These cells contain an enzyme, myeloperoxidase, whose microbicidal action is well documented. Polymorphonuclear cells do not display any specificity with respect to an antigen, but play an essential part in the case of acute inflammation, with antibodies and the complement system, in the host's defense against microorganisms. Their main function is phagocytosis. During this process, the microorganisms are included in vacuoles (phagosomes) which fuse with the granules containing myeloperoxidase to form phagolysosomes. During phagocytosis, the enzymatic activity of the myeloperoxidase leads to the formation of HOCl, a potent bactericidal compound (hypochlorous acid); this activity requires H.sub.2 O.sub.2 (hydrogen peroxide), which appears in the polymorphonuclear cell when it is stimulated by various agents, and in particular by the immunological reactions induced by microorganisms. Hypochlorous acid is oxidizing in itself, but produces still more strongly oxidizing derivatives chloramines. Finally, reacting with H.sub.2 O.sub.2, from which it is derived, hypochlorous acid produces an extremely oxidizing form of oxygen, singlet oxygen.
The major problem nevertheless lies at macrophage level. In effect, the macrophage is a very large cell, more robust than the polymorphonuclear cell and capable, like the latter, of phagocytosing microorganisms. It also possesses an H.sub.2 O.sub.2 -generating system but is not, however, capable of producing myeloperoxidase. This deficiency decreases its defensive efficacy. It has been discovered, however, according to the invention, that macrophages can incorporate and utilize myeloperoxidase, which remains active after penetration into the macrophages, an acquisition complementing in an effective manner their cytolytic and bacteriolytic arsenal, especially for the destruction of various infectious agents affecting immunosuppressed patients.
Although myeloperoxidase, once in the plasma, is taken up very quickly by the macrophages, specific administration systems delivering the enzyme in an optimal manner to the macrophages can be used according to the invention, producing myeloperoxidase conjugates by covalent coupling with a transporting agent possessing an affinity for macrophages. In this connection, there may be mentioned transporting agents such as mannosylated human albumin, as well as antibodies or antibody fragments, such as the Fc constant portion, directed towards receptors present on macrophages.
Other systems consist in coupling an antibody or Ab fragment specific for the macrophage to the enzyme human myeloperoxidase by non-covalent complexing or by DNA manipulation, to obtain an "immune complex".
The administration of such conjugates or immune complexes leads to targeting of the human MPO towards the macrophage, to its ingestion by phagocytosis and to release of the enzyme in active form within the macrophage, its preferential site of action, where it participates in combating infections.
In the case of immune complexes prepared by genetic engineering, DNA coding for MPO, the latter being active or in the form of a natural precursor, is coupled to DNA coding for an immunoglobulin fragment specifically recognizing macrophages.